Research Area. The long-term goal of this project is to determine whether maternal folic acid supplementation during pregnancy increases the risk of early childhood asthma and atopy. Supplementation with folic acid, synthetic folate, is recommended during the periconceptional period to prevent neural tube defects (NTD). Studies in different populations have suggested an association between reported folic acid supplementation during pregnancy and increased risk of infant lower respiratory tract infection and early childhood asthma, but data are limited. While adequate intake of folate is essential for prevention of NTDs, it is important to delineate the impact of supplementation on the risk of common respiratory and atopic diseases. Folate plays an important role in DNA methylation, a regulator of gene expression. A causal relationship between folic acid supplementation and respiratory outcomes in children has not been established. However, this relationship does have some biologic plausibility. In a pregnant mouse model, a diet high in methyl donors, including folate, resulted in an augmented allergic phenotype in the offspring, as seen in asthma. Opportunity and Impact. There is no primary prevention strategy for atopic diseases such as asthma. Our objective is to determine whether higher maternal folate intake or the timing of this intake increases the risk of wheezing, asthma, and other atopic diseases in children. This collective work will characterize maternal folate status using objective measures and will assess childhood wheezing, asthma, allergic rhinitis, and atopic dermatitis using validated tools and objective measures. This will be the first investigation in a country with a national fortification program, where individuals may have high intake of folic acid from the diet. Approach. This work will use complementary retrospective and prospective cohorts of mother-child pairs. Specific aim #1 will investigate the population-based incidence of wheezing and asthma during the first 6 years of life, by the timing of folic acid containing prescriptions filled during pregnancy in a retrospective cohort of 80,000 mother-child dyads from the Tennessee Medicaid population. Specific Aim #2 will determine if a) measured maternal plasma folate levels or b) reported folate intake is associated with prospective development of wheezing, asthma, and/or atopy in the first 5 years of life in mother-child dyads enrolled in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) cohort. Innovation and Sustainability. This innovative, cost-efficient project will have the advantages of 1) a well-characterized retrospective cohort with a large number of mother-child dyads and determination of folic acid prescriptions filled by month of pregnancy and 2) a prospective cohort that includes the rich, existing infrastructure of the CANDLE cohort with maternal and infant biospecimens, nutritional data, and prospective follow-up using validated tools and objective measures to assess respiratory and atopic outcomes. This study has potential to inform prenatal recommendations and identify modifiable risk factors for asthma and atopy.